MANNOSE & FUCOSE THERAPY

WHAT IT IS?

FIRST, the fucose therapy has everyone baby using female milk of healthy mothers.

In nutrition of the healthy man the carbohydrates should come up to 60 % out of the total caloricity of food. Usually everyone knows that human blood contains 80- 100 mg% of glucose. However, including the glucose, the blood of a healthy man must also contain other monosaccharums - mannose, fucose, ribose, arabinose, xylose and others.

These monosaccharums must be present in the human blood in the amount of 10 - 15 mg%.

But nobody has actually analysed their role in the human organism. In 1993-1994 we studied the composition of blood as per saccharums in a hundred of people (both healthy and with various illnesses) with the help of gas chromatography. [ 1 ]. We established that for various illnesses the level of these saccharums in patients' blood was various. The least quantity of these saccharums was spotted at the patients with cancer and diabetes mellitus.

In 1984-1987 we found again with the help of the gas chromatography, in female milk from 75 mothers that alongside with lactose, there was fucose and its derivatives in the amount of 8 - 15 % from the total volume of all saccharums [ 2 ]. It was detected that the female milk of some mothers did not contain fucose and its derivatives, and the pathology of their children development was also detected

Thus, in 1984 we have detected impairments in the carbohydrates composition of female milk and 10 years later, in 1993 we discovered similar disturbances in the carbohydrates composition in the blood of patients as well.

SECONDARY, the mannose therapy has everyone man using cellular-containing food with correct gastrointestinal tract.

At the use cellular - containing food in thick intestine at presence bifidobacteria there is a hydrolysis of mannane and galaktomannane and mannose then is soaked up and has in human blood.

At the use of food not cellular-containing structures (milk, cheese, cottage cheese, a flour of the premiums and et all) or at absence bifidobacteria in thick intestine is not exempted mannose and accordingly it hasn't in human blood.

Our researches since 1993 on studying the role of mannose and fucose deficiency in human organism have shown, that as a result of a long deterioration of their level as well as of some other minor sugars in human blood, there appears malfunction of synthesis of many carbohydrate structures. We found this malfunction in synthesis of glycoproteins - mucopolysaccharides, as well as in synthesis of glycoproteins - heparan sulfate II, but first of all these breakdowns are formed during synthesis of immune bodies (lymphocytes, phagocytes, antibodies, interleukines).

As the result we have patented our methods of restoration of malfunction of carbohydrate exchange due to introduction of mannose and-or fucose into human organism.

WHICH EFFECTS HAS MANNOSE & FUCOSE THERAPY NOW?

As we detected a diminished amount of these irreplaceable saccharums in the patients' blood [ 3 ], we began to supply human organism with these minor monosaccharum. We started to introduce these monosaccharum as food supplementations or as food, containing them, into nutrition of patients in 1993. We received stunning results [ 4 ]. The carbohydrate exchange of the patients with diabetes mellitus was normalized, and the level of blood glucose was stabilized alongside with the body's dropping requirement for exogenous insulin. Retinal microangiopathy, blood pressure of the patients with insulin - independent diabetes mellitus were also normalized, the immune system of the body got strengthened, cardiovascular system came in norm and depressed blood pressure came to the optimal level, many other morbid parameters were normalized [ 5 ].

All this allowed us to patent the new method of treatment of diabetes mellitus in Russia [ 6 ], and 2 years later we patented a new method of normalization of the carbohydrate exchange in various illnesses with the help of minor sugars in Russia [ 7 ].

Thus, in 1993 we patented a discovery in the field of medicine and biology concerning the role of minor saccharums in management of biochemical processes both in a healthy human organism and with diseases.

We discovered a new group of irreplaceable components of the vitamin type in human nutrition in regard both to quantity and effect.

Now they started to carry out similar researches in the USA, Denmark, England and France as I have sent the results of my investigation to NIH and other institutes and laboratories during last ten years.

We and much later some French scientists [ 8 ] established, that "mannose and other specific dietary sugars represent a new class of non essential nutrients displaying interesting roles". The American scientists together with scientists of other countries began to carry out an all-round research to study the role of mannose in treatment of carbohydrate-deficient glycoprotein syndrome type 1 [ 9, 10 ]. The oral mannose therapy persistently corrects the severe clinical symptoms and biochemical abnormalities of phosphomannose isomerase deficiency [ 11] and the results indicate that mannose therapy is used in attachment of S. zoo, P. aeruginosa and E. coli in uterine mucosal epithelium [12, 13].

Thus, my researches on the role of vitaminoid (receptor) saccharums in human organism [ 14 ] and their application for treatment of these or those illnesses are also confirmed by the scientists in many laboratories of the world.

WHICH EFFECTS WILL HAS MANNOSE & FUCOSE THERAPY IN FUTURE?

We shall be the further researches in the field of regulation of synthesis of the high mannose receptor due to introduction of mannose into of patients with various kinds of diseases at the example of synthesis of Immunoglobulin A, playing an important role in the protective barrier of human body against new diseases that appear on the planet and are more connected with breakdown of synthesis of Immunoglobulin A. It is, first of all, penetration of pathogenic microorganisms from other zoo-organisms through the protective barrier of human body consisting basically of the Immunoglobulin A (for example, SARS, HIV and others).

Experiments will be properly made proceeding from the existing concept on the role of vitaminoid sugars in human organism and arising malfunction due to absence or deficiency of their levels in human blood in biochemical and genetic processes. The noninvasive painless method of selection of the immunoglobulin A with patients with various biochemical malfunctions and the original method of detecting breakdowns in synthesis of its carbohydrate part will allow to understand the mechanism of occurrence of synthesis malfunction of the given antibodies. The received results will throw light on mechanisms of occurrence of malfunction in the high mannose reception system "Self"- "Nonself" and opportunities of regulation of synthesis of its carbohydrate part responsible for identification of a strange microorganism. It will allow to further understand the reasons of malfunction of this reception and to find means of managing the immune system.

WHAT IT IS HIGH MANNOSE RECEPTION SYSTEM "SELF"-"Nonself"?

The human immune system is created to protect the body against strange organisms and cells. Thus 'strangers' for our organism can be exterior microorganisms and viruses, cells of the body itself (cancer cells, cells with the broken reception system, abnormal cells, mechanically crushed cells etc.), as well as cell fragment with abnormal reception system (glycoproteins, glycolipids, lipoproteins etc.).

We call all these strange bodies, constructed genetically, antigens. As soon as these antigens enter the body, our protective system starts generating antibodies. How does our body determine that these antigens are 'strangers'? To fulfil this task the human body has an original system "self" - "non-self" [ 23 ]. This system is widely applied in military area to differentiate between self and non-self aeroplanes, self and non-self ships. But in the human body this system works much more effectively and is formed by multi-level duplication.

The "self" - "non-self" system works in the human body according to the following principle. At the approach of an immune cell to a 'stranger' there takes place an interaction of the high mannose receptor with the receptor of an unknown cell. If the receptors are identical, the immune system determines the unknown cell as 'self'. If the receptor of the unknown cell differs at least one molecule, all the destruction system gets switched on. This multi-level system in the human body is presented by complement system, macrophages, and specific immunity.

What is the basic structure of the cells receptors and immune system? On the cell surface there are receptor glycoproteins having the following high mannose carbohydrate structure - Man (9) ClcNAc (2) Fuc (1) [24, 25 ]. The same structure also exists on enzymes [ 26 ], vesicular-integral membrane protein [ 27 ] and other glycoprotein and glycolipid receptors.

If there is no similar receptor on the cell surface it will be destroyed. This is how our organism protects itself in order to survive in the medium of other organisms. Under the influence of biochemical processes in a human organism these carbohydrate structures can change.

At impairment of carbohydrate nutrition and malfunction of the gastrointestinal tract [ 28 ] there appears the fall down of the mannose level in human blood [ 29 ] and begins the synthesis of high mannose carbohydrate fragments with a lower amount of mannose molecules:

eight - Man (8) ClcNAc (2) Fuc (1) [ 30 ];

seven - Man (7) ClcNAc (2) Fuc (1) [ 26 ];

five - Man (5) ClcNAc (2) Fuc (1) [ 31 ];

three - Man (3) ClcNAc (2) Fuc (1) [ 32 ].

This decrease of the amount of mannose molecules in glycoproteins and glycolipids brings about breakdown of the reception system to its less branchy structure (see fig. 1-4).

Fig 1. Healthy cell with normal high mannose system of reception. This system consists of one molecule fucose, two molecules of N-acetylglucosamine and 9 molecules of mannose {Man(9)GlcNAc(2)Fuc(1)}. The cell receptor has a big branchy structure.

Fig 2. Cell with impairment in the reception system due to lack of blood mannose. One molecule of mannose is not synthesized in carbohydrate structure of the high mannose receptor {Man(8)GlcNAc(2)Fuc(1)}. The cell receptor has a less branchy structure.

Fig 3. Cell with impairment in the reception system due to long-time lack of blood mannose. Two molecules of mannose are not synthesized in the carbohydrate structure of the high mannose receptor {Man (7) GlcNAc (2) Fuc (1)}. The cell receptor has a little branchy structure.

Fig 4. Cell with impairment in the reception system because of long-lasting lack of blood mannose. Four molecules of mannose are not synthesized in the carbohydrate structure of the high mannose receptor {Man(5)GlcNAc(2)Fuc(1)}. The cell receptor has a weak branchy structure.

How fast are these impairments formed in our organism? The decrease of the amount of mannose molecules in the structure of the glycoprotein and glycolipid receptor doesn't result in the deviation of the cell reception system at once. As the life period of different cells in our organism is various, the first system to be broken is the reception system in immunoglobulins, leucocytes, erythrocytes and liver cells, the lifetime of which is from 2 to 120 days. Therefore the reduction of mannose level in the blood brings about impairment of the carbohydrate structure of reception in antibodies.

Protective functions of human body against infiltration of strange microorganisms and formation of abnormal cells in this case are reduced due to this broken reception. The further decrease of the mannose level in human blood causes formation of malfunction of carbohydrate structure of reception in other cells as well (beta cells, muscle, connective tissue and others). Decrease of the mannose level in human blood for a long period (10 - 50 years) results in formation of AIDS, cancer. In bodies of patients with AIDS the cell reception system, due to a high protein diet and long intake of antibiotics, advised by doctors, is broken to such an extent, that the reception system does not practically work because of lacking mannose [ 33 ].

What are the consequences of the mannose decrease in the glycoproteins and glycolipids receptors?

The reduction of the amount of mannose molecules in glycoprotein and glycolipid fragments of receptors result in impairment of many biochemical processes. Now these impairments are found out at practically all diseases. Obesity is connected with impairment of reception of insulin by muscle and hepatic cells. Diabetes mellitus is connected with impairment of carbohydrate structure of vesicles for deduction of insulin from beta cells at insulin-dependent diabetes and impairment of reception of insulin in liver cells at insulin-independent diabetes [ 34, 35 ]. It also results in dystrophy of retinal pigment epithelium [ 36 ], recurrent infections in adults [ 37 ] and other diseases and dysfunctions. The decrease of the amount of mannose molecules in the receptor structure results in development of meningococcal disease [ 38 ]; tuberculous meningitis [ 39 ] and others illnesses.

Is it possible to rapidly increase the concentration of mannose in human blood and, consequently, to quickly cure the patient? It is impossible. With the increase of mannose in blood first of all the glycoprotein and glycolipid receptors of antibodies with the boosted content of the mannose in their carbohydrate structure start to be synthesized. They begin to destroy all the cells, which have glycoprotein and glycolipid receptors with a smaller amount of mannose. In this case the autoimmune processes of human organism get activated. The immune cells of human body begin to destroy cells of the body with broken mannose reception, determining them as "non-self".

If there are not so many of such cells, the body temperature does not go up. The more cells determined as "non-self", the more intensive are the autoimmune processes of destruction of 'non-self' cells. Processes of killing various microorganisms and viruses that colonized the human organism due to weakening of the immune control, also take place. In this case the human body temperature can fast rise to critical. Therefore it is impossible to promptly cure patients with AIDS. They can be lost at once due to autoimmune diseases. For these patients it is necessary to raise the mannose level in blood slowly, in stages, without overloads during several years.

Thus, for synthesis of normal receptors in human body it is necessary to keep up the level of saccharum receptors (mannose, fucose, arabinose and others) in the blood either with the help of nutrition or with the help of the alimentary additives, and not to allow decreasing of mannose in blood for a long time. Besides the basic mannose reception "self" - "non-self" system, in human organism there are other additional systems based on fucose, arabinose. Thus, for modern medicine it is necessary not to block the activity of immune system with the help of antibiotics when there are no signs of infection by microorganisms, but to help the human body to activate the reliability of this system.

As the half-life of immunoglobulin A is only 6 days, it will be very good for investigation to study the activity of high mannose receptor by introducing mannose (fucose) into the patients' diet at the examples of the carbohydrate structure of immunoglobulin A.

Therefore support of basic biochemical researches on regulation of high mannose receptor activity "Self-Unself" immunoglobulin A by introduction of mannose to patients will be necessary for us.

References cited:

1. Chepurnoi I.P., Bolbat K.E. Modified method for gas chromatography of human blood sugars// Clinical laboratory diagnostic.-1997, N 1, p.31-32

2. Carbohydrate content of breast milk/ S.M.Kunizhew, I.P.Chepyrnoy et. all.-Problems of Nutrition (Rus.) 1985, n.4.- p.69-71

3. Disordered metabolism of mono- and disaccharides in diabetes mellitus/K.E.Bolbat, I.P.Chepurnoi // Problems of endocrinology (Russia).- M., Medicine, 1997, 43 (2), p.12-16

4. Correction with the help of minor sugars of infringement of the carbohydrate exchange at the patients with diabetes mellitus./I.P.Chepurnoy, K.E.Bolbat // First Russian diabetic congress.- Moscow, 1998.- p. 337

5. Chepurnoy I.P., Bolbat K.E. Method of treatment the diabetes mellitus. The patent N 2097041 G A 61 K 31/70 (Russia)

6. Chepurnoy I.P. Method of correction of carbohydrate metabolism in human organism (Variants). Patent N 2121353. G A 61 K 35/74, 31/70 (Russia)

7. Dietary specific sugars for serum protein enzymatic glycosylation in man // Berger V. et all. Metabolism 1998 Dec; 47 (12):1499-503

8. Carbohydrate-deficient glycoprotein syndrome type 1:correction of the glycosylation defect by deprivation of glucose or supplementation of mannose // Korner C. et all. Glycoconj J 1998 May; 15 (5):499-505

9. Carbohydrate-deficient glycoprotein syndrome type 1b. Phosphomannose isomerase deficiency and mannose therapy // Niehues R. et all. J Clin Invest 1998 Apr 1; 101 (7):1414-20

10. Failure of short-term mannose therapy of patients with carbohydrate-deficient glycoprotein syndrome type 1A // Kjaergaard S. et all. Acta Paediatr 1998 AUG; 87 (8):884-8

11. Oral mannose therapy persistently corrects the severe clinical symptoms and biochemical abnormalities of phosphomannose isomerase deficiency. //Harms HK et al. Acta Paediatr. 2002; 91(10):1065-72.

12. Effect of subminimal inhibitory concentrations of three fluoroquinolones on adherence of uropathogenic strains of Escherichia coli.// Baskin H, Dogan Y, Bahar IH, Yulug N. Int J Antimicrob Agents. 2002 Jan;19(1):79-82.

13. Wolff H, Panhans A, Stollz W, Meurer M. Adherence of Escherichia coli to sperm: a mannose mediated phenomenon leading to agglutination of sperm and E. coli. Fertil Steril 1993; 60: 154-8.

14. Chepurnoy I.P. Nutrition and Health.- Stavropol, Kavkazski krai, 1999.- 278 p.

15. Oligosaccharide seqyencing technology/ P.M.Rudd, G.R. Quile, B. Kuster, D.J.Harvey, Q. Opdenakker, R.A. Dwek//Nature, 1997, 388, p.205-207

16. Calls M.M. Guenzi S. Carelli S. Simmen T. Sparvoli A. Sitia R. IgM polymerization inhibits the Golgi-mediated processing of the mu-chain carboxy-terminal glycans. Molecular Immunology, 1996, 33 (1):15-24

17. Zavazal V., Krauz V., Kratzin H., Hilschmann N., Structure and function of IgE myeloma protein VL from an atopic patient/International Archives of Allergy and immunology, 1996, 110 (2), 143-8

18. Youssef HM., Doncel GF., Bassiouni BA., Acosta AA. Mannose-binding sites on human spermatozoa and sperm morphology/Fertility and Sterility, 1996, 66 (4):640-5

19. Schmitz B., Thiele J., Otto F., Thiele-Ochel S., Heedt T., Zensen U., Baldus SE.,Wickenhauser C., Fischer R. Interactions between endogeneous lectins and fucosylated oligosaccharides in megakaryocyte-dependent fibriplast growth of the normal bone marrow/Leukemia, 1996, 10 (10): 1604-14

20. Saitoh H. Takagaki K. Nakamura T. Munakata A. Yoshida Y. Endo M. Characterization of mucin in whole-gut lavage fluid obtained from patients with inflammatory bowel disease/Digestive Diseases and Sciences, 1996, 41 (9): 1768-74

21. Panneerselvam K., Freeze HH., Mannose corrects N-glycosylation in carbohydrate-deficient glycoprotein syndrome fibroblasts/Journal of Clinical Investigation, 1996, 97 (6):1478-87

22. Panneerselvam K. Freeze HH. Mannose enters mammalian cells using a specific transporter that is insensitive to glucose/Journal of Biological Chemistry, 1996, 271 (16):9417-21

23. Fraser IP, Koziel H, Ezekowitz RA The serum mannose-binding protein and the macrophage mannose receptor are pattern recognition molecules that link innate and adaptive immunity/Semin Immunol 1998 Oct; 10 (5):363-72

24. Gonzalez DS., Karaveg K, Vandersall-Nairn AS, Lal A, Moremen KW Identification, expression, and characterization of a cDNA encoding human endoplasmic reticulum mannosidase I, the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis/Biol Chem 1999 Jul 23; 274 (30):21375-86

25. Romero PA., Vallee F, Howell PL, Herscovics A Mutation of Arg(273) to Leu alters the specificity of the yeast N-glycan processing class I alpha1,2-mannosidase/Biol Chem 2000 Apr 14; 275 (15):11071-4

26. Matsuura F, Ohta M, Ioannou YA, Desnick RJ Human alpha-galactosidase A: characterization of the N-linked oligosaccharides on the intracellular and secreted glycoforms overexpressed by Chinese hamster ovary cells/Glycobiology 1998 Apr; 8 (4):329-39

27. Hara-Kuge S., Ohkura T, Seko A, Yamashita K Vesicular-integral membrane protein, VIP36, recognizes high-mannose type glycans containing alpha1-->2 mannosyl residues in MDCK cells/Glycobiology 1999 Aug; 9 (8):833-9

28. Klein N., Jack D Immunodeficiency and the gut: clues to the role of the immune system in gastrointestinal disease/Ital J Gastroenterol Hepatol 1999 Nov; 31 (8):802-6

29. Chepurnoy IP Problems of Nutrition (Rus) 1999 68 (3), p. 42-46

30. Vallee F., Lipari F, Yip P, Sleno B, Herscovics A, Howell PL Crystal structure of a class I alpha1,2-mannosidase involved in N-glycan processing and endoplasmic reticulum quality control/EMBO J 2000 Feb 15; 19 (4):581-8

31. Ohta M.,Ohnishi T, Ioannou YA, Hodgson ME, Matsuura F, Desnick RJ Human alpha-N-acetylgalactosaminidase: site occupancy and structure of N-linked oligosaccharides/Glycobiology 2000 Mar; 10 (3):251-61

32. Marchal I., Mir AM, Kmiecik D, Verbert A, Cacan R Use of inhibitors to characterize intermediates in the processing of N-glycans synthesized by insect cells: a metabolic study with Sf9 cell line/Glycobiology 1999 Jul; 9 (7):645-54

33. Koziel H., Eichbaum Q, Kruskal BA, Pinkston P, Rogers RA, Armstrong MY, Richards FF, Rose RM, Ezekowitz RA Reduced binding and phagocytosis of Pneumocystis carinii by alveolar macrophages from persons infected with HIV-1 correlates with mannose receptor downregulation/J Clin Invest 1998 Oct 1; 102 (7):1332-44

34. Disordered metabolism of mono- and disaccharides in diabetes mellitus/K.E.Bolbat, I.P.Chepurnoi//Problems of endocrinology.- M., Medicine, 1997, 43 (2), p.12-16

35. Frick W., Bauer A, Bauer J, Wied S, Muller G Structure-activity relationship of synthetic phosphoinositolglycans mimicking metabolic insulin action/ Biochemistry 1998 Sep 22; 37 38):13421-36

36. Wilt SD., Greaton CJ, Lutz DA, McLAUGHLIN BJ Mannose Receptor is Expressed in Normal and Dystrophic Retinal Pigment Epithelium/Exp Eye Res 1999 Oct; 69 (4):405-411

37. Kakkanaiah VN, Shen GQ, Ojo-Amaize EA, Peter JB Association of low concentrations of serum mannose-binding protein with recurrent infections in adults/Clin Diagn Lab Immunol 1998 May; 5 (3):319-21

38. Bax WA, Cluysenaer OJ, Bartelink AK, Aerts PC, Ezekowitz RA, van Dijk H Association of familial deficiency of mannose-binding lectin and meningococcal disease/ Lancet 1999 Sep 25; 354 (9184):1094-5

39. Mannose-binding protein B allele confers protection against tuberculous meningitis. Hoal-Van Helden EG, Epstein J, Victor TC, Hon D, Lewis LA, Beyers N, Zurakowski D, Ezekowitz AB, Van Helden PD /Pediatr Res 1999 Apr; 45 (4 Pt 1):459-64